It is known that pyrimidine-4,6-dicarboxylic acid diamides and 2,4-substituted pyridine N-oxides inhibit the enzymes proline hydroxylase and lysine hydroxylase and thereby bring about an inhibition of collagen biosynthesis by exerting an influence on the collagen-specific hydroxylation reaction (EP 0418797; EP 0463592). This inhibition of collagen biosynthesis results in the formation of a nonfunctional, under-hydroxylated collagen molecule which the cells can only release into the extracellular space in small quantity. In addition, the under-hydroxylated collagen cannot be incorporated into the collagen matrix and is very readily degraded proteolytically. As a consequence of these effects, the overall quantity of collagen which is deposited extracellularly decreases. It is known from patent applications WO 02/064571 and WO 02/064080, that certain pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides can be allosteric inhibitors of MMP 13.
In diseases such as osteoarthritis and rheumatism, destruction of the joint takes place, with this destruction being caused, in particular, by the proteolytic breakdown of collagen due to collagenases. Collagenases belong to the metalloproteinase (MP) or matrix metalloproteinase (MMP) superfamily. Under physiological conditions, MMPs cleave collagen, laminin, proteoglycans, elastin or gelatin and therefore play an important role in bone and connective tissue. A large number of different inhibitors of the MMPs and/or collagenases have been disclosed (EP 0 606 046; WO 94/28889). Known MMP inhibitors frequently suffer from the disadvantage of lacking the specificity involved in inhibiting only one class of MMPs. As a result, most MMP inhibitors inhibit several MMPs simultaneously because the structure of the catalytic domain in the MMPs is similar. As a consequence, the inhibitors have the undesirable property of acting on many enzymes, including those which have a vital function (Massova I., et al., The FASEB Journal (1998) 12, 1075–1095).
Michael Murray showed that compounds which contain an unsubstituted benzo[1,3]dioxole ring as a radical inhibit the cytochrome P450 liver enzymes (Michael Murray, Current Drug Metabolism 2000, 67–84). Said radical is held to be responsible for these significant toxicological effects.
In an endeavor to find effective compounds for treating connective tissue diseases, it has now been found that the compounds which are employed in accordance with the invention are powerful inhibitors of matrix metalloproteinase 13 while essentially having no effect on MMPs 3 and 8.